Bilirubin inhibits the anticancer activity of sorafenib by blocking MCL-1 degradation in hepatocellular carcinoma cells

Objective:Sorafenib is a first-line drug for advanced hepatocellular carcinoma(HCC).Unfortunately,most patients with HCC do not respond to sorafenib,mainly because of the frequent development of drug resistance.Bilirubin is an end metabolite of heme catabolism and an indicator of liver function,but its direct role in regulating the anticancer activity of sorafenib in HCC cells is unclear.In the current study,we aimed to investigate the mechanism of action of bilirubin in sorafenib-mediated tumor suppression in HCC.Methods:A retrospective observational cohort of 100 patients receiving sorafenib was conducted to evaluate the potential role of bilirubin in predicting the prognosis of patients with HCC.Human HCC cell lines were treated with sorafenib in the absence or presence of bilirubin,and cell proliferation,apoptosis,and signaling pathways were assayed.The antagonistic effect of bilirubin toward sorafenib was assessed in nude mice bearing HCC xenografts.Results:Serum levels of bilirubin(including total,direct,and indirect bilirubin)negatively correlated with the overall survival of patients with HCC treated with sorafenib(P<0.05).Both in vitro and in vivo analyses demonstrated that bilirubin significantly abrogated sorafenib-mediated proliferation inhibition and apoptosis induction in HCC cells(P<0.05).Mechanically,bilirubin inhibited sorafenib-induced activation of GSK-3βand subsequent downstream MCL-1 degradation.Conclusions:Our study provides experimental evidence of the antagonistic effect of bilirubin toward sorafenib-mediated anticancer activity in HCC,and it suggests that bilirubin could be used to predict the efficacy of sorafenib treatment.

Blockade of NMT1 enzymatic activity inhibits N-myristoylation of VILIP3 protein and suppresses liver cancer progression

Hepatocellular carcinoma(HCC)is one of the most common malignant tumors.Identification of the underlying mechanism of HCC progression and exploration of new therapeutic drugs are urgently needed.Here,a compound library consisting of 419 FDA-approved drugs was taken to screen potential anticancer drugs.A series of functional assays showed that desloratadine,an antiallergic drug,can repress proliferation in HCC cell lines,cell-derived xenograft(CDX),patient-derived organoid(PDO)and patient-derived xenograft(PDX)models.N-myristoyl transferase 1(NMT1)was identified as a target protein of desloratadine by drug affinity responsive target stability(DARTS)and surface plasmon resonance(SPR)assays.Upregulation of NMT1 expression enhanced but NMT1 knockdown suppressed tumor growth in vitro and in vivo.Metabolic labeling and mass spectrometry analyses revealed that Visinin-like protein 3(VILIP3)was a new substrate of NMT1 in protein N-myristoylation modification,and high NMT1 or VILIP3 expression was associated with advanced stages and poor survival in HCC.Mechanistically,desloratadine binds to Asn-246 in NMT1 and inhibits its enzymatic activity,disrupting the NMT1-mediated myristoylation of the VILIP3 protein and subsequent NFκB/Bcl-2 signaling.Conclusively,this study demonstrates that desloratadine may be a novel anticancer drug and that NMT1-mediated myristoylation contributes to HCC progression and is a potential biomarker and therapeutic target in HCC.

RNF6 promotes chronic myelogenous leukemia cell proliferation and migration by stabilizing vimentin via multiple atypical ubiquitinations

Chronic myelogenous leukemia(CML)is a malignancy from bone marrow myeloid stem cells mainly driven by the fusion gene BCR-ABL.In addition to BCR-ABL,other genes including RNF6 are also dysregulated in CML cells.1 RNF6,a ubiquitin ligase of the RING family,promotes various cancer cell proliferation,chemoresistance,and tumor growth in vivo by targeting various proteins for ubiquitination and degradation,including SHP1,TLE3,FOXA1,and MAD1.^(2) However,its specific mechanism in CML is not known.

Silencing MYH9 blocks HBx-induced GSK3βubiquitination and degradation to inhibit tumor stemness in hepatocellular carcinoma

MYH9 has dual functions in tumors.However,its role in inducing tumor stemness in hepatocellular carcinoma(HCC)is not yet determined.Here,we found that MYH9 is an effective promoter of tumor stemness that facilitates hepatocellular carcinoma pathogenesis.Importantly,targeting MYH9 remarkably improved the survival of hepatocellular carcinoma-bearing mice and promoted sorafenib sensitivity of hepatocellular carcinoma cells in vivo.Mechanistic analysis suggested that MYH9 interacted with GSK3βand reduced its protein expression by ubiquitin-mediated degradation,which therefore dysregulated theβ-catenin destruction complex and induced the downstream tumor stemness phenotype,epithelial–mesenchymal transition,and c-Jun signaling in HCC.C-Jun transcriptionally stimulated MYH9 expression and formed an MYH9/GSK3β/β-catenin/c-Jun feedback loop.X protein is a hepatitis B virus(HBV)-encoded key oncogenic protein that promotes HCC pathogenesis.Interestingly,we observed that HBV X protein(HBX)interacted with MYH9 and induced its expression by modulating GSK3β/β-catenin/c-Jun signaling.Targeting MYH9 blocked HBX-induced GSK3βubiquitination to activate theβ-catenin destruction complex and suppressed cancer stemness and EMT.Based on TCGA database analysis,MYH9 was found to be elevated and conferred poor prognosis for hepatocellular carcinoma patients.In clinical samples,high MYH9 expression levels predicted poor prognosis of hepatocellular carcinoma patients.These findings identify the suppression of MYH9 as an alternative approach for the effective eradication of CSC properties to inhibit cancer migration,invasion,growth,and sorafenib resistance in HCC patients.Our study demonstrated that MYH9 is a crucial therapeutic target in HCC.

KCTD4 interacts with CLIC1 to disrupt calcium homeostasis and promote metastasis in esophageal cancer

Increasing evidences suggest the important role of calcium homeostasis in hallmarks of cancer,but its function and regulatory network in metastasis remain unclear.A comprehensive investigation of key regulators in cancer metastasis is urgently needed.Transcriptome sequencing(RNA-seq)of primary esophageal squamous cell carcinoma(ESCC)and matched metastatic tissues and a series of gain/loss-of-function experiments identified potassium channel tetramerization domain containing 4(KCTD4)as a driver of cancer metastasis.KCTD4 expression was found upregulated in metastatic ESCC.High KCTD4 expression is associated with poor prognosis in patients with ESCC and contributes to cancer metastasis in vitro and in vivo.Mechanistically,KCTD4 binds to CLIC1 and disrupts its dimerization,thus increasing intracellular Ca^(2+)level to enhance NFATc1-dependent fibronectin transcription.KCTD4-induced fibronectin secretion activates fibroblasts in a paracrine manner,which in turn promotes cancer cell invasion via MMP24 signaling as positive feedback.Furthermore,a lead compound K279-0738 significantly suppresses cancer metastasis by targeting the KCTD4-CLIC1 interaction,providing a potential therapeutic strategy.Taken together,our study not only uncovers KCTD4 as a regulator of calcium homeostasis,but also reveals KCTD4/CLIC1-Ca^(2+)-NFATc1-fibronectin signaling as a novel mechanism of cancer metastasis.These findings validate KCTD4 as a potential prognostic biomarker and therapeutic target for ESCC.

Stabilization of MYC G-quadruplex DNA by ruthenium(II)complex overcomes imatinib resistance in chronic myeloid leukemia cells harboring T315I mutation

The key pathogenesis of chronic myeloid leukemia(CML)is the formation of BCR-ABL fusion gene,encoding a 210 kDa Bcr-Abl tyrosine kinase,which is crucial for the occurrence and development of CML.Imatinib(IM)is the first targeted anticancer drug approved by FDA for the treatment of CML;however,some patients,especially those in accelerated phase and blastic phase,develop primary or secondary drug resistance to IM.Particularly,the most challenging resistance is caused by T315I mutation of Bcr-Abl,which represents approximately 15%–20%of all acquired mutations and renders cell resistant to a variety of tyrosine kinase inhibitors.1,2 Thus,there is an urgent need to develop novel strategies to overcome Bcr-Abl T315I-meidated IM resistance.

The dual role of ferroptosis in pancreatic cancer: a narrative review

Pancreatic ductal adenocarcinoma is the main cause of cancer-related mortality,with a lack of effective treatments and overall survival rates far lower than other solid cancers.This clinical challenge is related to late diagnosis as well as primary or acquired resistance to therapy-induced apoptosis.Targeting nonapoptotic cell death pathways may provide alternative therapeutic strategies to overcome drug resistance.In particular,recent studies have suggested that ferroptosis,a type of iron-dependent nonapoptotic cell death,is a promising target for pancreatic ductal adenocarcinoma.Ferroptosis can be triggered by inhibiting or activating the redox or iron metabolism-related pathways,mediated by extrinsic/membrane transports(e.g.,solute carrier family 7 member 11)or intrinsic/enzymes(e.g.,glutathione peroxidase 4).Although the exact effector molecule remains obscure,reactive oxygen species-induced lipid peroxidation and subsequent plasma membrane damage appears to play a central role in mediating ferroptotic death.While treatment-induced ferroptosis is beneficial to suppress tumor growth,inflammation-related immunosuppression caused by ferroptotic damage may promote the occurrence of pancreatic ductal adenocarcinoma.In this review,we outline the latest knowledge about the regulation and function of ferroptosis in pancreatic tumorigenesis and therapy.

VPS33B suppresses lung adenocarcinoma metastasis and chemoresistance to cisplatin

The presence of VPS33B in tumors has rarely been reported.Downregulated VPS33B protein expression is an unfavorable factor that promotes the pathogenesis of lung adenocar-cinoma(LUAD).Overexpressed VPS33B was shown to reduce the migration,invasion,metas-tasis,and chemoresistance of LUAD cells to cisplatin(DDP)in vivo and in vitro.Mechanistic analyses have indicated that VPS33B first suppresses epidermal growth factor receptor(EGFR)Ras/ERK signaling,which further reduces the expression of the oncogenic factor C-Myc.Down-regulated c-Myc expression reduces the rate at which it binds the p53 promoter and weakens its transcription inhibition;therefore,decreased C-Myc stimulates p53 expression,leading to decreased epithelial-to-mesenchymal transition(EMT)signal.NESG1 has been shown to be an unfavorable indicator of non-small-cell lung cancer(NSCLC).Here,NESG1 Was identified as an interactive protein of VPS33B.In addition,NESG1 was found to exhibit mutual stimulation with VPS33B via reduced RAS/ERK/c-Jun-mediated transcription repression.Knockdown of NESG1 activated EGFR/Ras/ERK/c-Myc signaling and further downregulated p53 expression,which thus activated EMT signaling and promoted LUAD migration and invasion.Finally,we observed that nicotine suppressed VPS33B expression by inducing PI3K/AKT/c-Jun-mediated transcription suppression.Our study demonstrates that VPS33B as a tumor suppressor is signif-icantly involved in the pathogenesis of LUAD.

Bilirubin inhibits lung carcinogenesis by up-regulating cystatin A expression in tumor-infiltrating macrophages

As one of the leading causes of cancer deaths worldwide,the pathogenesis of lung cancer is still not completely understood.Bilirubin,a product of heme metabolism,has long been considered a waste product of the body.Increasing evidence suggests that bilirubin has additional antioxidant,anti-inflammatory,and proteasome inhibitory activities.However,the specific role of bilirubin in the formation and development of lung cancer has not been elucidated.

Pharmacological insights into autophagy modulation in autoimmune diseases

As a cellular bulk degradation and survival mechanism,autophagy is implicated in diverse biological processes.Genome-wide association studies have revealed the link between autophagy gene polymorphisms and susceptibility of autoimmune diseases including systemic lupus erythematosus(SLE)and inflammatory bowel disease(IBD),indicating that autophagy dysregulation may be involved in the development of autoimmune diseases.A series of autophagy modulators have displayed protective effects on autoimmune disease models,highlighting the emerging role of autophagy modulators in treating autoimmune diseases.This review explores the roles of autophagy in the autoimmune diseases,with emphasis on four major autoimmune diseases[SLE,rheumatoid arthritis(RA),IBD,and experimental autoimmune encephalomyelitis(EAE)].More importantly,the therapeutic potentials of small molecular autophagy modulators(including autophagy inducers and inhibitors)on autoimmune diseases are comprehensively analyzed.

Chemical compound cinobufotalin potently induces FOXO1-stimulated cisplatin sensitivity by antagonizing its binding partner MYH9

In this study,we present novel molecular mechanisms by which FOXO1 functions as a tumor suppressor to prevent the pathogenesis of nasopharyngeal carcinoma(NPC).First,we observed that FOXO1 not only controlled tumor stemness and metastasis,but also sensitized NPC cells to cisplatin(DDP)in vitro and in vivo.Mechanistic studies demonstrated that FOXO1-induced miR-200b expression through the GSK3β/β-catenin/TCF4 network-mediated stimulation of ZEB1,which reduced tumor stemness and the epithelial–mesenchymal transition(EMT)signal.Furthermore,we observed FOXO1 interaction with MYH9 and suppression of MYH9 expression by modulating the PI3K/AKT/c-Myc/P53/miR-133a-3p pathway.Decreased MYH9 expression not only reduced its interactions with GSK3β,but also attenuated TRAF6 expression,which then decreased the ubiquitin-mediated degradation of GSK3βprotein.Increased GSK3βexpression stimulated theβ-catenin/TCF4/ZEB1/miR-200b network,which increased the downstream tumor stemness and EMT signals.Subsequently,we observed that chemically synthesized cinobufotalin(CB)strongly increased FOXO1-induced DDP chemosensitivity by reducing MYH9 expression,and the reduction in MYH9 modulated GSK3β/β-catenin and its downstream tumor stemness and EMT signal in NPC.In clinical samples,the combination of low FOXO1 expression and high MYH9 expression indicated the worst overall survival rates.Our studies demonstrated that CB potently induced FOXO1-mediated DDP sensitivity by antagonizing its binding partner MYH9 to modulate tumor stemness in NPC.

Cancer stem cell-mediated therapeutic resistance in hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is a highly heterogeneous malignancy.In the clinic,therapeutic resistance is largely attributed to tumor heterogeneity.Growing evidence indicates that cancer stem cells(CSCs)are the major source of tumor heterogeneity.Hence,uncovering the resistance mechanisms associated with CSC properties is essential for developing effective therapeutics.CSCs resemble embryonic stem cells.Embryonic developmentrelated genes and signaling pathways are usually abnormally active and function as oncofetal drivers in HCC.Multiple strategies have been applied to identify oncofetal drivers.The mechanisms of CSC resistance could also provide reliable biomarkers to predict treatment failure.Precisely targeting these specific CSC properties may be effective in preventing or annihilating therapy resistance.This review provides an overview of drug resistance mechanisms associated with CSC traits and summarize therapeutic strategies against drug resistance.